Targeting of sebaceous follicles as a treatment of sebaceous gland disorders

ABSTRACT

Laser treatments of sebaceous gland disorders with laser sensitive dyes are disclosed. A preferred laser treatment includes topical application of an energy activatable material to the skin followed by laser irradiation.

BACKGROUND OF THE INVENTION

Skin disorders, such as acne, can be irritating and embarrassing. Themajor disease of skin associated with sebaceous follicles, is acnevulgaris. This is also the most common reason for visiting adermatologist in the United States. There are many treatments, but nocures for acne. These include antibiotics (which inhibit growth of p.acnes bacteria which play a role in acne), retinoids such as Accutane®(isotetinoin, which reduces sebaceous gland output of sebum), andantimicrobials such as benzoyl peroxide. Acne lesions result from therupture of a sebaceous follicle, followed by inflammation and pus (a“whitehead”), or by accumulation of plugged material in the sebaceousfollicle (a “blackhead”). This pathophysiology has two majorrequirements: (1) plugging of the upper portion of the follicle, and (2)an increase in sebum production. The upper portion of the follicle,i.e., the “pore” into which sebum is secreted and which is directly incommunication with the skin surface, is called the infundibulum. A plugforms in the infundibulum from cells, sebum, bacteria, and other debris.The sebaceous gland continues to produce sebum (an oily fluid),stretching the infundibulum until either it or some lower portion of thefollicles ruptures.

Generally, only a minority of sebaceous hair follicles on the face andupper back develop acne lesions. Therefore, it is likely that somestructural differentiation predisposes a fraction of the follicles todevelop acne. In most males, acne is worst in the teenage years and thensubsides, suggesting that a subpopulation of follicles may be presentwhich ultimately self-destruct. In women, teenage acne is often followedby menstrual acne flares well into adulthood. Since both plugging of theinfundibulum and high sebaceous gland activity are necessary for an acnelesion to develop, it is likely that the predisposing factors for thefollicles which become infected are (1) an infundibulum shape which iseasily plugged, and/or (2) a hyperactive sebaceous gland.

Unlike medical dermatology, most laser dermatology treatments areactually “cures”—producing a permanent anatomic, microsurgical effect onthe skin. This includes skin resurfacing, portwine stain treatment,tattoo and pigmented lesion removal, and hair removal. Selectivephotothermolysis or controlled skin ablation with lasers or otherextremely intense light sources, might therefore be capable of curingskin disorders, such as acne, if appropriately targeted to the primarysite(s) of pathophysiology.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery thatenergy activatable materials, such as chromophores, described infra, incombination with an energy source, e.g., photo (light) therapy, can beused to treat sebaceous gland disorders, e.g., eliminate, inhibit, orprevent occurrence or reoccurrence of the skin disorder. A preferredexample of such a sebaceous gland disorder is acne.

The present invention pertains to methods for treating skin disordersassociated with sebaceous follicles by topically applying an energyactivatable material to a section of skin afflicted with a sebaceousgland disorder, wherein the material is activated by energy whichpenetrates outer layers of epidermis. A sufficient amount of thematerial infiltrates the afflicted section of skin and is exposed tosufficient energy to cause the material to become photochemically orphotothermally activated, thereby treating the sebaceous gland disorder.In one embodiment, the sebaceous gland disorder is acne. Suitable energysources include flash lamp based sources and lasers, such as Nd: YAG,Alexandrite, flash lamp-pumped dyes and diodes. Alternatively, theenergy source can also be a continuous wave energy source. In preferredembodiments, the energy activatable material is a laser sensitivechromophore, e.g., a chromophore which is capable of beingphotostimulated by a laser, e.g., a dye. In a particularly preferredembodiment, the chromophore is methylene blue.

The present invention also pertains to methods for modifying the openingto the infundibulum by topically applying an energy activatable materialto the opening to the infundibulum, wherein the material is activated byenergy which penetrates outer layers of epidermis. A sufficient amountof the material infiltrates spaces about the infundibulum and theinfundibulum is exposed to sufficient energy to cause the material tobecome photochemically or photothermally activated, thereby modifyingthe opening to the infundibulum. In one embodiment, the opening to theinfundibulum is enlarged. In another embodiment, the opening to theinfundibulum is decreased. In still another embodiment, the opening tothe infundibulum is altered such that pore pluggage will not occur,e.g., the infundibulum is reshaped such that excess sebum, oils, dirtand bacteria will not cause pore pluggage to occur, resulting in a blackhead (comedon) or white head (milium).

The present invention also pertains to methods for down regulating,e.g., decreasing, the oil/lipid output production of the sebaceousgland. Application of the energy activatable material to thepilosebaceous unit, e.g., the sebaceous gland, followed by stimulationby an energy source can cause selective permanent physical alteration tothe sebaceous gland and/or follicle such that surrounding tissue remainsunaffected. The physical alteration to the sebaceous gland and/orfollicle results in diminished production of sebum.

The present invention further pertains to methods for modifying thepilosebaceous unit by topically applying an energy activatable materialto the pilosebaceous unit, wherein the material is activated by energywhich penetrates into the dermis and into the outer layers of epidermis.A sufficient amount of the material infiltrates the pilosebaceous unitand the pilosebaceous unit is exposed to sufficient energy to cause thematerial to become photochemically or photothermally activated, therebymodifying the pilosebaceous unit. In one embodiment, the pilosebaceousunit is treated such that sebum production is diminished. A decrease inpore pluggage can occur, as a result of the diminishment of sebumproduction. In one preferred embodiment, treatment of the pilosebaceousunit by the present invention results in elimination of pore pluggage,e.g., the pilosebaceous unit is treated such that excess sebum, oils,dirt and bacteria will not cause pore pluggage to occur, resulting in ablack or white head.

BRIEF DESCRIPTION OF THE DRAWINGS

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawings will be provided by the Patentand Trademark Office upon request and payment of the necessary fee.

FIG. 1 is a cross-sectional view of hair shafts with pore pluggage andenergy activatable material.

FIG. 2 is a cross-sectional view of a plugged follicle after an energyactivatable material has been allowed to penetrate the follicle andsebaceous gland.

FIG. 3 is a cross-sectional view of hair shafts which include an energyactivatable material during irradiation with an energy source, e.g., alaser.

FIGS. 4a and 4 b are cross-sectional views of hair shafts where the poreopening and infundibulum are modified by the process of the invention.

FIG. 5a and 5 b are cross-sectional views of hair shafts where sebaceousglands are modified by the process of the invention.

FIGS. 6a and 6 b are cross-sectional views of hair shafts where debriswithin the pore is removed by the process of the invention.

FIGS. 7a and 7 b are cross-sectional views of hair shafts where the poreopening, infundibulum and sebaceous glands are modified by the processof the invention and where debris within the pore is also removed.

FIG. 8 is a color photograph of light microscopy of blue staining of theepidermis, sebaceous glands and hair follicles.

FIG. 9 is a color photograph of light microscopy of blue staining of theepidermis, sebaceous glands and hair follicles.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention will now be moreparticularly described and p pointed out in the claims. It will beunderstood that the particular embodiments of the invention are shown byway of illustration and not as limitations of the invention. Theprinciple e features of this invention can be employed in variousembodiments without departing from the scope of the invention.

The present invention is based, at least in part, on the discovery thatenergy activatable materials, such as chromophores, described infra, incombination w with an energy source, e.g., photo (light) therapy, can beused to treat sebaceous gland disorders, e.g., eliminate, remove, orprevent occurrence or reoccurrence of the sebaceous gland disorder.Examples of such sebaceous gland disorders include sebaceous glandhyperplasia, acne vulgaris and acne rosacea. A preferred example of sucha sebaceous gland disorder is acne.

In one aspect, the present invention is drawn to methods for treatingsebaceous gland disorders by topically applying an energy activatablematerial to a section of skin afflicted with a sebaceous gland disorder.The energy activatable material is energetically stimulated by an energysource. For example, the energy activatable material can be achromophore which absorbs at least one frequency band of energy whichpenetrates outer layers of epidermis. A sufficient amount of thematerial infiltrates the skin and the section of skin is exposed to atleast one frequency band of energy so as to impart, to the material,sufficient energy to cause the ma material to become photochemically orphotothermally activated which brings about a physiological change,thereby treating the sebaceous gland disorder. In one embodiment, thesebaceous gland disorder is acne. Suitable energy sources include a widerange of electromagnetic sources including, energy emitted by the sun,Rf (radio frequency) energy, energy from microwave generators,ultraviolet light generators, flash lamp based sources and lasers, suchas Nd: YAG, Alexandrite, and flash lamp-pumped dyes and diodes.Alternatively, the energy source can be a continuous wave energy source.In preferred embodiments, the energy activatable material is a lasersensitive chromophore, e.g., a chromophore which is capable of beingphotostimulated by a laser. In a particularly preferred embodiment, thechromophore is methylene blue.

The present invention also pertains to methods for modifying the openingto the infundibulum by topically applying an energy activatable materialto the opening to the infundibulum, wherein the material absorbs atleast one frequency band of energy which penetrates outer layers ofepidermis. A sufficient amount of the material infiltrates spaces aboutthe infundibulum and the section of skin is exposed to at least onefrequency band of energy so as to impart to the material, sufficientenergy to cause the material to become photochemically or photothermallyactivated, thereby modifying the opening to the infundibulum. In oneembodiment, the opening to the infundibulum is altered such that porepluggage will not occur, e.g., the infundibulum is reshaped such thatexcess sebum, oils, dirt and bacteria will not cause pore pluggage tooccur, resulting in a blackhead (comedon) or white head (milium). In apreferred embodiment, the opening to the infundibulum is opened.

The present invention further pertains to methods for modifying thepilosebaceous unit by topically applying an energy activatable materialto the pilosebaceous unit, wherein the material absorbs at least onefrequency band of energy which penetrates outer layers of epidermis. Asufficient amount of the material infiltrates the pilosebaceous unit andthe section of skin is exposed with at least one frequency band ofenergy so as to impart to the material, sufficient energy to cause thematerial to become photochemically or photothermally activated, therebymodifying the pilosebaceous unit. In one embodiment, the pilosebaceousunit is treated such that sebum production is diminished, therebyresulting in decreased pore pluggage. In one preferred embodiment,treatment of the pilosebaceous unit by the present invention results inelimination of pore pluggage, e.g., the pilosebaceous unit is treatedsuch that excess sebum, oils, dirt and bacteria will not cause porepluggage to occur, resulting in a black or white head.

Sebaceous glands are components of the pilosebaceous unit. They arelocated throughout the body, especially on the face and upper trunk, andproduce sebum, a lipid-rich secretion that coats the hair and theepidermal surface. Sebaceous glands are involved in the pathogenesis ofseveral diseases, the most frequent one being acne vulgaris. Acne is amultifactorial disease characterized by the occlusion of follicles byplugs made out of abnormally shed keratinocytes of the infundibulum(upper portion of the hair follicle) in the setting of excess sebumproduction by hyperactive sebaceous glands. Various treatment modalitiesfor acne exist that aim in modifying the rate of sebum secretion by thesebaceous glands (e.g., retinoids), inhibiting the bacterial overgrowthin the follicular duct (antibiotics), or decreasing the inflammation ofacne lesions (anti-inflammatory agents). Most of these agents are notcurative of acne and simply control the disease by affecting one of theaforementioned pathogenic factors. Oral retinoids are a notableexception: they are potent drugs that can achieve a significant curerate for acne, but their side effect profile often limits their use.Advantages of the present invention include that treatment canpermanently alter the pilosebaceous unit, rendering it no longersusceptible to pore pluggage without the side effects associated withoral retinoids.

The term “sebaceous gland disorders” is intended to include thosesebaceous gland disorders which can be treated by an energy activatablematerial. The energy activatable material can be a photothermally orphotochemically activatable, e.g., reactive, material which issusceptible to photoactivation or stimulation, e.g., light, i.e., laserstimulation. The activation or excitation of the material generatesreactive species, such as radicals, which can interact with the site ofpore pluggage, inflammation, bacteria, viruses, etc. and promote, forexample, oxidation of those agents which are associated with thedisorder. Examples of sebaceous gland disorders which can be treated bythe methods of the invention include sebaceous gland hyperplasia, acnevulgaris and acne rosacea. Of particular importance is treatment of acneby the method of the invention.

The term “pluggage” is intended to obstruction of the pores by thebuildup of sebum, dirt, bacteria, mites, oils, and/or cosmetics in thepore, e.g., about the infundibulum.

The term “acne” is art recognized and is intended to include acnevulgaris and acne rosacea. Acne vulgaris the most common skin diseaseseen in dermatologic practice which affects approximately 17 millionpeople in the United States. Its precise cause is unknown, althoughabnormal keratin production with obstruction of the follicular opening,increased production of sebum (lipids secreted by the androgen-sensitivesebaceous glands), proliferation of Propionibacterium acnes (anaerobicfollicular diphtheroids), follicular rupture and follicular mites(demodex) are commonly associated with acne.

Skin conditions such as acne are believed to be caused or exacerbated byexcessive sebum flow produced by sebaceous glands most of which areadjacent to and discharge sebum into, hair follicles. Sebum is composedof keratin, fat, wax and cellular debris. Sebum forms a moist, oily,acidic film that is mildly antibacterial and antifungal and may to someextent protect the skin against drying. It is known that the bacteriawhich contribute to acne, Propionibacterium acnes or (P-acnes), grows insebum. Significant sebum flow in humans begins at puberty. This is whenacne problems generally arise.

The phrase “energy activatable material” is intended to include thoseagents which, when stimulated by energy from an energy source, e.g., alaser source, become energetically stimulated, e.g., photothermally orphotochemically. These materials can be stimulated by various energysources, e.g., electromagnetic sources, such as a continuous wavesource, a laser source, flashlamp, ultraviolet light, microwaves,infrared light, etc. The material absorbs the energy which causes thematerial to become thermally or chemically active.

Suitable materials useful in the invention include metal oxides, such asaluminum oxide, iron oxides, carbon particles (graphite and amorphouscarbon particles) and natural and synthetic chromophores. The term“chromophore” is art recognized and is intended to include thosecompounds which absorb energy at a given wavelength, often by sites ofunsaturation, carbon-oxygen bonds, and/or charged species, orcombinations thereof. Suitable chromophoric groups include nitro groups,azo, quinoids, alkylene units, carbonyls, esters, alkynes, aldehydes,carboxylic acids, and those groups associated with n→π* and π→π*transitions. Preferred energy activatable materials include lasersensitive dyes, for example, methylene blue, indocyanine green and thosein U.S. Pat. No. 4,651,739, issued Mar. 24, 1987, the entire contents ofwhich are incorporated herein by reference. Preferred dyes are thosedyes which are activated by laser stimulation. Preferred laser sensitivedyes are those which are FDA approved. A preferred dye, a lasersensitive dye, is methylene blue. In one embodiment, the laser sensitivedye is not indocyanine green. In another embodiment, the energyactivatable material is not carbon particles.

The energy activatable materials of the present invention undergoenergetic activation, by photothermal or photochemical stimulation. Theterm “photothermal” interaction (excitation or stimulation) is artrecognized and is intended to include interactions which are due toconversion of energy into heat. Photothermal activation of an energyactivatable material causes the material to be heated, thereby heatingthe local area, preferably selectively with a significant temperatureincrease of such that unwanted material, e.g., tissues, oils, bacteria,viruses, dirt, etc. such that the surrounding tissue remains unaffected,The photothermally activated material can form biologically reactiveproducts. Photothermal processes can involve oxidation of, for example,cell walls, extracellular matrix components, nuclei, etc. As a result ofphotothermal stimulation, the infundibulum can be reshaped as a resultof collagen shrinkage. Additionally, the process can cause cell death inthe sebaceous gland, thereby decreasing production of sebum.

The term “photochemical” is art recognized and is intended to includemolecular bond breaking where one or more absorbed photon excites themolecule to a higher electronic, vibrational, or rotational state.Photochemical stimulation of an energy activatable material causes thematerial to enter an excited energy state wherein energy is absorbed,e.g., by the chromophore, whereby bonds within the energy activatablematerial are broken and forms reactive by products such as radicalspecies. These reactive by products can interact with the localizedsurrounding tissue area such that the tissue is cleansed of unwantedmaterial, e.g., oils, bacteria, viruses, dirt, etc. As a result ofphotochemical stimulation, the infundibulum can be reshaped as a resultof collagen shrinkage. Additionally, the photochemical process can causecell death in the sebaceous gland, thereby decreasing production ofsebum.

The photochemically activated material can return to the ground state orit can decompose into biologically reactive fragments. Photochemicalprocesses can involve oxidation or radical polymerization of, forexample, cell walls, extracellular matrix components, nuclei, etc.

Photochemical activation of energy activatable materials can be achievedover long time periods with energy of low intensity. For example,treatment of sebaceous gland disorders could be treated with an energyactivatable material contained in a cream or lotion applied to the skinprior to long periods of exposure to the sunlight, e.g., whileparticipating in sports or sitting on the beach.

The energy activatable materials of the present invention do not undergofragmentation or vaporization such that the energy activatable materialcauses photo-mechanical destruction of the surrounding tissue, e.g., theenergy activatable materials do not undergo violent decomposition, i.e.,the energy activatable materials do not explode. Preferably, therefore,the energy activatable material is subjected to a sufficient energywhich causes the energy activatable material to be photochemically orphotothermally stimulated without violent decomposition and harm tosurrounding tissue (See for example Ton G. van Leeuwen et al.Optical-Thermal Response of Laser-Irradiated Tissue, “Pulsed LaserAblation of Soft Tissue” ed. A. J. Welch and M. J. C. van Gemert,Chapter 21, pg 709, Plenum Press, New York, 1995).

Not to be limited by theory, stimulation of the energy activatablematerial, e.g., a chromophoric agent, can cause oxidation anddecomposition of the unwanted material(s), thereby degrading andremoving unwanted material from the pore. Additionally, this treatmentcan also cause the opening to the infundibulum to become modified, e.g.,the pore opening is enlarged or the pore opening is constricted orclosed. Consequently, alteration of the pore opening, such asenlargement of the pore opening, a change in the pore shape, orconstriction of the pore opening prevents unwanted dirt, bacteria,viruses and/or oils from building up in the treated area, e.g., theinfundibulum.

Photothermal alteration of the sebaceous gland, the follicleinfundibulum, or both requires the deposition of sufficient energy tocause local heating to temperatures capable of cell killing (e.g.,killing of sebocytes, stem cells, or bacterial cells), proteindenaturation (e.g., denaturation of basement membranes and/orperifollicular collagen), or vaporizatsion of tissue. In general, thesetemperatures range from about 60-100° C. for the first two effects, andsomewhat over 100° C. (e.g., about 120° C.) for vaporization of tissue.

The amount of a light-absorbing dye which must be present for a givenlocal fluence of a pulse of optical energy to cause these photothermaleffects, can be determined by considering the basic principles ofselective photothermolysis. If the pulse of optical radiation isdelivered within the thermal relaxation time for the target structure,heat flow from the target is limited during the pulse. The preferredpulse duration is therefore about equal to or less than the thermalrelaxation time of the given target, which measured in seconds isapproximately equal to the square of the target's shortest dimensionmeasured in millimeters. For example, the infundibulum portion of mostsebaceous follicles on the face is approximately 0.3 mm in diameter,which corresponds approximately to a thermal relaxation time of about0.1 seconds (100 ms).

The sebaceous gland is similar in diameter, but may on the nose be aslarge as 1 mm. Although thermal confinement is achieved with pulsesshorter than the target's thermal relaxation time, very short pulsescause unwanted mechanical injury which can rupture the follicles. Forexample, the method of Tankovich, U.S. Pat. Nos. 5,752,949, 5,425,728,5,226,907 and 5,752,948, employs explosive, photomechanical mechanism todamage hair follicles. Skin eruption has been observed on patients withan acne-like skin caused by the Tankovich treatment.

The fatty acids, sebum, and bacteria present in sebaceous follicles isextremely irritating if not contained by the follicle. In acne vulgaris,rupture of the follicle is the event which stimulates inflammation toform a “pimple”, including accumulation of pus to form a “whitehead”. Itis therefore desired to avoid rupture of the follicle or sebaceos gland.Such mechanical injury can be avoided by using pulses longer than about0.1 milliseconds. Thus, the preferred range of pulse duration is 0.1-100ms, and the ideal pulse duration is about 10-50 ms.

When thermal confinement during the pulse is achieved, the localtemperature rise is given approximately by ΔT=Eμ(ρc)⁻¹, where E is thelocal fluence at the target, μ is the local absorption coefficient ofthe target, and ρc is heat capacity of the target. It is highlypreferred to use wavelengths of the optical spectrum in which naturalskin pigments exhibit weaker absorption (to minimize heating at othersites), and which penetrate well to the anatomic depth of theinfundibulum and/or sebaceous glands. The orange, red, and near-infraredwavelength region (600-1200 nm) is therefore most appropriate. At thesewavelengths, there is very little absorption by natural skin pigmentsother than melanin.

Melanin is often present in coarse hairs, but in general is absent ornearly absent in the vellus hairs present in the sebaceous folliclesassociated with acne vulgaris. The exception to this is when a“blackhead” (an open comedo) is present, which consists of a pluggedsebaceous follicle containing melanin or melanin-like oxidizedsubstances which absorb light. To a reasonable approximation, therefore,there is no optical absorption in the 600-1200 nm wavelength region inmost sebaceous follicles. The tolerable fluence for human skin of anoptical pulse in this part of the spectrum is about 5-100 J/cm²,depending on the amount of epidermal melanin and on wavelength.

Skin surface-cooling methods can also be used to increase this tolerablefluence. Ideally, an amount of dye can be taken up by the sebaceousfollicle such that a pulse delivering less than 100 J/cm² can producedesired photothermal effects. The target absorption coefficient, μ, isapproximately equal to 2.3, times the local molar concentration [d] ofthe dye in the follicle, times the molar extinction coefficent ε forthat dye. The value of ρc for most tissues is about 4 Jcm⁻³C⁻¹. Manydyes have molar extinction coefficients of 10³-10⁵M⁻¹cm⁻¹.

From this information, the local dye concentration needed in thefollicle can be estimated, and used to direct therapy. For example, toreach a temperature of approximately 80° C., a temperature rise ΔT wouldbe about 50° C. because the ambient skin temperature is typically about30° C. At a fluence of E=10 J/cm² (easily tolerated by most skin types),the local value of μ must therefore be about μ=ΔTρc/E=(50)(4)(10), or 20cm³¹ ¹. The concentration of a dye to achieve this absorptioncoefficient at the target, can be determined. Preferred dyes such asmethylene blue have molar extinction coefficients about ε=10⁴M⁻¹cm³¹ ¹,which require uptake to a dye concentration [d] in the follicle of about[d]=μ/(2.3ε)=20/(2.3×10⁴), or about 10⁻³M.

Thus, about 1 mM concentration of these dyes is sufficient to achievethe desired photothermal effects to inhibit acne vulgaris. Because afactor of 10 was allowed in the tolerable fluence in the above example,it would be possible (minimally) to practice the invention with valuesof μ as low as about 2 cm⁻¹, corresponding to dye concentration of about0.1 mM (100 μM). However, it is preferred in practice to provide asafety margin between the fluence necessary for the desired photothermaleffect on sebaceous glands and/or infundibulum, and the maximum fluencetolerated by human skin. The preferred dye concentration in the follicleinfundibulum and/or sebaceous gland is therefore greater than 0.1 mM formost of the preferred dyes, and more generally a sufficientconcentration to achieve a local absorption coefficient of greater thanabout 10 cm⁻¹.

Preferably, the energy source produces an exposure area of between about3 to about 100 millimeters to treat a section of skin afflicted with asebaceous gland disorder, as described above. The fluence is limitedsuch that the skin is not damaged while the sebaceous gland disorder istreated, e.g., eradicated, inhibited, or prevented. The fluence iscontrolled such that localized destruction to the undesired sebaceousgland disorder occurs with little or no non-specific necrosis ofsurrounding tissue. For example, at 755 nm, up to 100 J/cm² can beadministered to a very fair Caucasian individual without damage to theskin. The amount of energy a darker skin could tolerate without damageto the skin would be less. A person having skill in this art canascertain the amount of energy and type of energy to be expended toachieve the results desired.

Suitable energy sources include light-emitting diodes, incandescentlamps, xenon arc lamps, lasers or sunlight. Suitable examples ofcontinuous wave apparatus include, for example, diodes. Suitable flashlamps include, for example pulse dye lasers and Alexandrite lasers.Representative lasers having wavelengths strongly absorbed bychromophores, e.g., laser sensitive dyes, within the epidermis andinfundibulum but not sebaceous gland, include the short-pulsed red dyelaser (504 and 510 nm), the copper vapor laser (511 nm) and theQ-switched neodymium (Nd):YAG laser having a wavelength of 1064 nm thatcan also be frequency doubled using a potassium diphosphate crystal toproduce visible green light having a wavelength of 532 nm. Furtherexamples of lasers which are suitable for use as energy sources includethose in the following table of lasers:

Types of Laser Commercial Laser Types, Organized by WavelengthWavelength, μm Type Output type and power 0.523 Doubled Nd-YLF Pulsed,watts 0.532 Doubled Nd-YAG Pulsed to 50 W or CW to watts 0.534, 0.538He-Cd CW, milliwatts, in white-light laser 0.5435 He-Ne CW, 1-mW range0.578 Copper vapor Pulsed, tens of watts 400-700 nm Pulsed Dye tens ofJoules 514.5 nm Ar Ion tens of watts 530.9 nm Kr Ion approximately 5watts 750-900 nm GaAlAs semiconductor tens of watts depending on diodearray number of elements 1060 nm Nd:YAG tens of watts

Another desirable property of thermal and photochemical energyactivatable material is an absorption spectrum in the range of 600-1300nm; this minimizes surrounding blood from absorbing light intended forthe material (hemoglobin absorbs most strongly at the violet end of thespectrum).

The depth of penetration of the energy, e.g., light, emitted from theenergy source, such as a laser, is dependent upon its wavelength.Wavelengths in the visible to near IR have the best penetration and aretherefore best for use to treat the sebaceous gland and infundibulumlocated within the dermis.

Photochemical cell killing preferably uses chromophores with peakabsorbance in the 600-1300 nm range. Whether photostability is importantdepends on the mechanism of photochemical cell killing. For example,chromophores which kill by the interaction with oxygen to producesinglet state oxygen, high photostability is desirable, so that suchproduction continues for as long as possible before the chromophorebreaks down.

For chromophores which kill by virtue of the degradation of thechromophore to a toxic reaction product, photostability is generally notdesired, since the breakdown of the chromophore is the process whichachieves the desired effect.

In the present process, selective photoactivation is employed whereby anenergy (light) source, e.g., a laser, is matched with a wave-length tothe absorption spectrum of the selected energy activatable material,preferably a chromophoric agent, e.g., methylene blue at 661 nm. Forexample, an energy activatable material, adapted to accumulateselectively in the infundibulum and/or the sebaceous gland, is firstapplied to the region of afflicted skin to be treated. Followingabsorption of the energy activatable material, the accumulated material,is exposed to an energy source, e.g., a laser, capable of producing awavelength readily absorbed by the energy activatable material therebyselectively photothermally heating or photochemically treating thoseregions of the dermis known to have trapped oils, bacteria, viruses,dirt, etc. i.e., the pilosebaceous unit which includes the pore opening,infundibulum and sebaceous gland. Because the energy activatablematerial is selectively concentrated within or about these undesireddeposits, the deposits are degraded by the heat and/or radical speciesgenerated from the energy activated material. There is minimal to nodestruction of normal adjacent epidermal and dermal structures.

Preferably, the treatment of the invention modifies the pore opening tothe infundibulum such that the geometry, e.g., the shape, of the openingis permanently altered. Adjustment of the concentration of the energyactivatable material and the amount of energy applied by the energysource effects constriction, closure, or opening of the pore, therebypreventing accumulation of dirt, oils, bacteria, or viruses in thatfollicle. The operator will need to assess the parameters to illicit thedesired effect and will be determined on a patient by patient basis.Generally, it is most desirable to alter the shape of the pore, leavingthe pore enlarged and no longer prone to buildup of sebum and/or foreignmaterials which would cause pore pluggage.

As previously stated, the present invention involves the use of energysources, e.g., lasers, to target sebaceous glands and cause theirphotothermal or photochemical destruction. Sebaceous glands are mainlycomposed of amorphous lipid material and do not contain any obviousendogenous chromophores. In order to achieve selective photocoagulationof sebaceous glands and confine the extent of thermal injury in thesurrounding tissue, a topically applied energy activatable material withselective distribution to the pilosebaceous unit can be utilized. Theintroduction of a energy activatable material in sebaceous glandsfollowed by exposure to energy (light) with a wavelength thatcorresponds to the absorption peak of the chromophore, will increase thelocal absorption of light in tissue and lead to selective thermal damageof sebaceous glands.

The infundibulum is a critical site in the pathogenesis of many of thedisease states, especially acne. There is evidence that abnormalproliferation and desquamation of infundibular keratinocytes leads tothe formation of microcomedones and, later on, to clinically visiblefollicular “plugs” or comedones. Clinically, it appears that somesebaceous follicles are more prone than others to develop acne lesions,possibly due to an inherent structural difference or functionalabnormality of the infundibulum, that predisposes them to form plugs andocclude. The self-resolving nature of acne in most patients may reflectthe elimination of such “acne-prone” follicles which are eventuallyreplaced by normal skin or fibrosis after repeated bouts ofinflammation. If the architecture of the infundibulum is important inthe pathogenesis of acne, then selective destruction of this portion ofthe follicle through energy activatable material-assisted energy, e.g.,laser, targeting can help eliminate or correct the “pathologic” site bycreating a distended follicular opening that is able to extrude anyoccluded material.

The process of selective energy activation according to the presentinvention uses energy sources, e.g., light, e.g., lasers, matched to aparticular energy activatable material. In the case of photothermalactivation, to facilitate temperature rise, the pulse duration timeperiod should be shorter than that of the thermal relaxation time forthe energy activatable material. The thermal relaxation time is definedas the time it takes for a structure to cool to 50% of its peaktemperature immediately following exposure to a light source capable ofproviding enough energy to photoactivate the chromophore. Therefore,selective treatment of those dermal regions containing an energyactivatable material, e.g., a laser sensitive dye, will occur whenexposed to millisecond light pulses. A laser delivering pulses in therange of 1 to 50 milliseconds (ms) has been found to adequatelyphotoactivate energy activatable materials, such as carbon particles,iron oxide particles and laser sensitive dyes, e.g., chromophoricmaterials, deposited within the hair follicle matrix, e.g., about theinfundibulum and sebaceous gland. Different types of energy activatablematerials require variations in the energy dose applied and the type ofenergy source necessary to effect treatment of the afflicted skin area.When applied to the skin of the region to be treated, the energyactivatable material is absorbed within the hair follicle matrix andupon exposure, the energy will be concentrated in those critical areasof the follicle matrix where the energy activatable material hascollected e.g., the pilosebaceous unit including the sebaceous gland,infundibulum and pore opening.

Delivery of the energy activatable material, preferably methylene blueor other FDA approved dyes, to the follicle matrix can be achieved bytopical application, injection, liposome encapsulation technology,massage, iontophoresis or ultrasonic technology, or other means fordelivery of compounds into the dermal region of the skin, e.g.,pharmaceutically acceptable carriers.

The phrase “pharmaceutically acceptable carrier” as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a energy activatablematerial of the present invention within or to the subject such that itcan performs its intended function. Each carrier must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not injurious to the patient. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include: sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients, such as cocoa butter andsuppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such aspropylene glycol; polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. Preferredcarriers include those which are capable of entering a pore by surfaceaction and solvent transport such that the energy activatable materialis carried into or about the pore, e.g., into the sebaceous gland, tothe plug, into the infundibulum and/or into the sebaceous gland andinfundibulum.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening and perfuming agents, preservativesand antioxidants can also be present in the compositions.

Liquid dosage forms for topical administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, creams, lotions, ointments, suspensions and syrups. Inaddition to the active ingredient, the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor, peach,almond and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

The term “cream” is art recognized and is intended to include semi-solidemulsion systems which contain both an oil and water. Oil in watercreams are water miscible and are well absorbed into the skin, AqueousCream BP. Water in oil (oily) creams are immiscible with water and,therefore, more difficult to remove from the skin. These creams areemollients, lubricate and moisturize, e.g., Oily Cream BP. Both systemsrequire the addition of either a a natural or a synthetic surfactant oremulsifier.

The term “ointment” is art recognized and is intended to include thosesystems which have oil or grease as their continuous phase. Ointmentsare semi-solid anhydrous substances and are occlusive, emollient andprotective. Ointments restrict transepidermal water loss and aretherefore hydrating and moisturizing. Ointments can be divided into twomain groups- fatty, e.g., White soft paraffin (petrolatum, Vaseline),and water soluble, e.g., Macrogol (polyethylene glycol) Ointment BP.

The term “lotion” is art recognized and is intended to include thosesolutions typically used in dermatological applications.

The term “gel” is art recognized and is intended to include semi-solidpermutations gelled with high molecular weight polymers, e.g.,carboxypolymethylene (Carbomer BP) or methylcellulose, and can beregarded as semi-plastic aqueous lotions. They are typically non-greasy,water miscible, easy to apply and wash off, and are especially suitablefor treating hairy parts of the body.

In a one embodiment, liposomes are used to deliver the energyactivatable material to the follicle matrix. Liposomes providesite-specific transdermal delivery to the follicle matrix. In thisembodiment, the energy activatable material is microencapsulated withinthe liposome and topically applied to the epidermis of the skin.

As noted above, the carrier according to the present invention involvesencapsulating the effective amount of energy activatable material withina specific liposome to provide for efficient transdermal delivery of theenergy activatable material through the layers of the skin. Theseliposomal compositions are topically applied to the skin and deliver theencapsulated energy activatable material to the follicle regionincluding the sebaceous gland and infundibulum. Following delivery ofthe energy activatable material, irradiation results in highly specifictargeting of the follicle matrix and destruction of oils, dirt,bacteria, mites, or viruses within the infected area.

Liposomes are microscopic spherical membrane-enclosed vesicles or sacks(0.5-500 μm in diameter) made artificially in the laboratory using avariety of methods. Within the scope of the present invention, theliposomes should be non-toxic to living cells and they should deliverthe contents, in this case an energy activatable material, into thefollicle and immediately surrounding tissue. The liposomes according tothe present invention may be of various sizes and may comprise eitherone or several membrane layers separating the internal and externalcompartments.

The liposomes may be made from natural and synthetic phospholipids, andglycolipids and other lipids and lipid congeners; cholesterol,cholesterol derivatives and other cholesterol congeners; charged specieswhich impart a net charge to the membrane; reactive species which canreact after liposome formation to link additional molecules to thelysome membrane; and other lipid soluble compounds which have chemicalor biological activities.

A general discussion of the liposomes and liposome technology can befound in an article entitled, “Liposomes” by Marc J. Ostro, published inSCIENTIFIC AMERICAN, January 1987, Vol. 256, pp. 102-111 and in a threevolume work entitled, “Liposome Technology” edited by G. Gregorriadis,1984, published by CRC press, Boca Raton, Fla. the pertinent portions ofwhich are incorporated herein by reference.

FIG. 1 illustrates multiple hair shafts 10 (vellus) projecting below theepidermis region 12 of the skin and into the dermis 14 region. Eachshaft 10 extends down the follicle 16. The follicle includes a sebaceousgland 20 and which at the anagen stage of the hair cycle furtherincludes a papilla 18. The papilla 18 is supplied with small bloodvessels (not shown) that provide the growing hair with nourishment. Thefollicle 16 includes the pore opening 22 and the infundibulum 24, shownwith a plug 26 of dead cells, oils, bacteria and/or viruses. Topicalapplication of an energy activatable material 28 penetrates the poreopening 22 and infundibulum 24 and into the sebaceous gland 20 as shownin FIGS. 1 and 2.

In order to assure removal of plug 26, modification of pore opening 22,modification of the infundibulum 24, and/or modification of thesebaceous gland 20, use of a light source, e.g., a laser, havingsufficient energy and depth of penetration is required. FIG. 3demonstrates how an operator (not shown) will position the energy source30, e.g., a laser, over a hair follicle 16 such that an optimum locationfor aiming the light pulse to strike the energy activatable material 28about the plug 26, sebaceous gland 20, infundibulum 24 and/or poreopening 22 is obtained. The energy source 30 can be moved across theskin surface in any direction 32 by the operator, thereby effectivelyirradiating multiple follicles 16 multiple times. The process can berepeated until the desired effect(s) are achieved.

FIGS. 4a and 4 b demonstrate the effect(s) of the presently describedtreatment on the infundibulum 24. FIG. 4a depicts infundibulum 24 priorto treatment with an energy activatable material 28 and stimulation withan energy source 30. FIG. 4b depicts the same infundibulum 24 posttreatment whereby the shape of the infundibulum 24 and pore opening 22have been modified.

FIGS. 5a and 5 b demonstrate the effect(s) of the presently describedtreatment on the sebaceous gland 20. FIG. 5a depicts the sebaceous gland20 prior to treatment with an energy activatable material 28 andstimulation with an energy source 30. FIG. 5b depicts the same sebaceousgland 20 post treatment, whereby the size of sebaceous gland 20 has beendecreased.

FIGS. 6a and 6 b demonstrate the effect(s) of the presently describedtreatment on a plugged pore 26. FIG. 6a depicts the plug 26 prior totreatment with an energy activatable material 28 and stimulation with anenergy source 30. FIG. 6b depicts the same region of the infundibulum 24post treatment, whereby the plug 26 has been treated such that unwantedmaterial(s) has been removed from infundibulum 24.

FIGS. 7a and 7 b further demonstrate the effect(s) of the presentlydescribed treatment on a plugged pore 26, infundibulum 24, pore opening22, and sebaceous gland 20. FIG. 7a depicts the skin area prior totreatment with an energy activatable material 28 and stimulation with anenergy source 30. FIG. 7b depicts the same region of the skin posttreatment, whereby the plug 26 has been treated such that unwantedmaterial(s) has been removed from infundibulum 24 and the infundibulum24, pore opening 22 and sebaceous gland 20 have been modified.

Stimulation of the energy activatable material 28 will cause activationto occur, e.g., photothermnolysis and/or photochemical reactions, todisrupt the trapped cells, sebum, bacteria, mites, etc. located in thesebaceous gland 20 and/or the infundibulum 24. An advantage of thisprocess is that only tissue having energy activatable material willundergo photothermal or photochemical reactions. Surrounding tissuewhich does not include energy activatable material will not be adverselyaffected by this treatment.

Natural chromophores present in sebaceous follicles or follicular plugsare not sufficiently distinct from other chromophores of the dermis andepidermis to allow specific absorption. However, the infundibulum andsebaceous glands are directly accessible from the skin surface through a“pore” (the follicle opening), which allows topically-appliedsubstances, such as energy activatable materials, to enter thesestructures. Therefore, energy activatable materials orparticle-suspensions can be used to provide high, local, and specificabsorption after uptake into the infundibulum and/or sebaceous gland.

Energy activatable materials which enter the sebaceous follicles, suchas methylene blue (a lipophilic, cationic, FDA-approved dye is taken upinto human sebaceous follicles, and distributed over time into thesebaceous glands), can be used to target either the infundibulum, or thesebaceous glands depending on time after application, or both.

Topically-applied energy activatable materials initially enter theinfundibulum and later distribute to the sebaceous glands. It ispossible to actively drive those materials or chromophoric particlesinto the follicles by massage, pressure, ultrasound, or iontophoresis,after topically applying the chromophore to the skin surface. Methyleneblue, for example, can be rapidly driven into sebaceous follicles andeccrine sweat ducts by iontophoresis. Wiping the surface with or withouta solvent after delivery into the follicles, can be used to removeresidual material from the skin surface. Thus, after appropriateapplication and wiping, the energy activatable material, e.g., achromophore, can be preferentially located in follicles, within theinfundibular or the infundibular and sebaceous glands.

Either photothermal (i.e. using principles of selectivephotothermolysis) or photochemical (i.e., using principles ofphotodynamic therapy) mechanisms are utilized to affect the targetstructures, as a treatment to prevent sebaceous gland disorders, such asacne lesions, from forming. Methylene blue (MB) and many other lightsensitive chromophores are potent photodynamic photosensitizers and canalso be used as photothermal sensitizers. The red absorption maximum ofmethylene blue around 660 nm provides strong absorption for eithermechanism. Another strong candidate dye is indocyanine green (ICG)(Cardiogreen^(R), Becton-Dickenson), which has very poor photodynamicactivity but is an excellent photothermal chromophore. Indocyanine greenis a zwitterion (neutral, highly polar molecule) which tends to bindstrongly to proteins and is well suited for targeting the infundibulumby photothermal mechanisms. ICG absorbs maximally near 800 nm, awavelength well suited for diode, Alexandrite lasers, and other lightsources. For selective photothermolysis, pulses of intense red ornear-infrared light in the ms time domain at the appropriate wavelengthregion should be delivered, for example using a pulsed dye laser, diodelaser arrays, other pulsed or scanned lasers, or filtered flashlampsources to deliver flounces in excess of 1 J/cm² per pulse. Forphotodynamic effects, lower average irradiance exposures given overlonger exposure time would be appropriate for example approximately10-100 mW/cm² delivered for about 100-2000 seconds (total fluence, 1-200J/cm²). For photodynamic effect, light sources such as light-emittingdiodes, incandescent lamps, xenon arc lamps, lasers or sunlight can beused.

In order to form and retain a plug within the infundibulum, there mustbe a constriction along the outflow tract. As material including sebum,cells, or bacteria accumulate and are concentrated onto the plug, wallsof the infundibulum are dilated until the middle or lower part of theinfundibulum is larger in diameter than its outlet (the surface pore).If the outlet diameter can be increased, the plug is more likely to beexpelled and pressure within the sebaceous follicle decreased beforerupture can occur. The upper region of the infundibulum is also thesource of follicular neck cells which shed into the infundibulum and addto the plug. For these reasons, the walls of the upper portion of theinfundibulum and especially its pore at the skin surface are the primarytarget for energy activatable material-assisted sebaceous gland disordertreatment, e.g. acne treatment. In a manner conceptually similar tolaser skin “resurfacing”, the shape and size of the infundibulum and itsoutlet pore can be affected by energy activatable material-assistedphotothermal or photochemical treatment. The dermis immediatelysurrounding sebaceous follicles, is largely responsible for maintainingshape of the infundibulum, and should be altered to produce a permanentaffect. By using pulses in the ms time domain, there is time for thermalconduction from energy activatable material in the infundibulum, to thewall and immediately-surrounding dermal collagen of the infundibulum.Photothermal mechanisms are preferred because permanent changes areknown to be induced in the dermis.

The invention is further illustrated by the following examples which inno way should be construed as being further limiting. The contents ofall references, pending patent applications and published patentapplications, cited throughout this application, including thosereferenced in the background section, are hereby incorporated byreference. It should be understood that the models used throughout theexamples are accepted models and that the demonstration of efficacy inthese models is predictive of efficacy in humans.

EXEMPLIFICATION

Fresh, in-vitro human sebaceous skin samples were used. Dye solutionsand particle suspensions were applied to the samples at differentconcentration and in various vehicles, followed by localization of thedye by frozen sectioning and light microscopy. A number of FDA-approvedlaser sensitive dyes were examined and found that methylene blue andseveral others rapidly enter the infundibulum. Methylene blue proceededto deeply and selectively stain the sebaceous glands, requiring severalhours to do so. Apparently, almost any dye or suspension can bedelivered to the upper infundibulum by direct solvent flow into thepore. Optimization of the concentration and solvent for MB and ICG canbe determined by one skilled in the art. The effect of iontophoresis ofMB in vitro should increase rate of uptake by at least one order ofmagnitude. Physical means of increasing dye uptake into theinfundibulum, including ultrasonication with a tissue dismembranator atlow intensity, and a simple pressure-applicator intended to open thesurface pores while providing a pressure gradient in favor of dye uptakeis possible.

For MB dye, a 660 nm source is required, preferably a pulsed dye laseroperating with at least 1 ms pulse duration. There is essentially noabsorption by MB at wavelengths longer than 690 nm, such that ruby andAlexandrite lasers are not useful. Similar in-vitro laser targeting canbe performed using ICG in the infundibulum, and C-particle suspension(medical grade India Ink) to indicate that physical means deliversufficient chromophore into the infundibulum.

EXPERIMENTALS

Experiment Using Methylene Blue to Stain Sebaceous Glands in Ex VivoTissue

Freshly excised human skin from a face-lift procedure was provided by aplastic surgeon. The skin originated from the periauricular area and theanterior hairline of a middle-aged fair-skinned female. The samples werestored at 4° C. overnight. On the day of experiment, the tissue wasshaved with a razor and defatted by rubbing the surface with alcoholswabs for 1 minute. After cutting the skin in smaller pieces, the tissuewas placed on saline-soaked gauzes. Methylene blue, a cationichydrophilic dye was dissolved in distilled water, alcohol, and propyleneglycol at a concentration of 5% and applied on the surface of the skinin a thick layer at 31° C. After 1 hour, the excess dye was removed witha dry absorbing gauze revealing a lightly stained epidermis withaccentuation of the staining in the follicular pores in all specimen. 5mm-punch biopsies were performed and the samples were processed forfrozen sections.

Light microscopy of the histologic sections dense blue staining of theepidermis and of some sebaceous glands and entire hair follicles (FIG.8). There was minimal non-specific staining of the interstitial dermis.

Freshly excised human skin from a face-lift procedure was provided by aplastic surgeon. The skin originated from the periauricular area and theanterior hairline of a middle-aged fair-skinned female. The samples werestored at 4° C. overnight. On the day of experiment, the tissue wasshaved with a razor and defatted by rubbing the surface with alcoholswabs for 1 minute. After cutting the skin in smaller pieces, the tissuewas placed on saline-soaked gauzes. Methylene blue, a cationichydrophilic dye was dissolved in distilled water, alcohol, and propyleneglycol at a concentration of 5% and was mixed in a commerciallyavailable aqueous-based lotion (50μL of dissolved dye in 500 mg oflotion) and applied on the surface of the skin in a thick layer at 31°C. After 1 hour, the excess dye was removed with a dry absorbing gauzerevealing a lightly stained epidermis with accentuation of the stainingin the follicular pores in all specimen. 5 mm-punch biopsies wereperformed and the samples were processed fro frozen sections.

Light microscopy of the histologic sections dense blue staining of theepidermis and of some sebaceous glands and entire hair follicles (FIG.9). There was minimal non-specific staining of the interstitial dermis.

Methylene blue dye was also administered into the sebaceous glands viaRetina Gel®(Ortho Pharmaceuticals) as the carrier vehicle. Typically, asufficient amount of methylene blue (50 μL of dissolved dye in 500 mg ofgel) was combined with hydroxyproply cellulose, butylated hydroxytolueneand alcohol and applied to the epidermis. Penetration of the methyleneblue dye into the sebaceous glands of freshly excised human skin wasnoted via light microscopy as described above.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, many equivalents to specificembodiments of the invention described specifically herein. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

What is claimed is:
 1. A method for treating a sebaceous gland disordercomprising the steps of a) topically applying a chromophore containinggroup to a section of skin afflicted with a sebaceous gland disorder,wherein said chromophore containing group is activated by energy whichpenetrates outer layers of epidermis, b) causing a sufficient amount ofsaid chromophore containing group to infiltrate into spaces in saidskin; and c) exposing said section of skin to energy sufficient to causesaid chromophore containing group to become photochemically orphotothermally activated, thereby treating said sebaceous glanddisorder.
 2. The method of claim 1, wherein said chromophore containinggroup is methylene blue.
 3. The method of claim 1, wherein saidchromophore containing group is a laser sensitive material.
 4. Themethod of claim 3, wherein said laser sensitive material is methyleneblue.
 5. The method of claim 1, wherein said chromophore containinggroup is suspended in a pharmaceutical carrier.
 6. The method of claim5, wherein said pharmaceutical carrier is a liposome.
 7. The method ofclaim 6, wherein said pharmaceutical carrier is an oil.
 8. The method ofclaim 7, wherein said oil is baby oil.
 9. The method of claim 1, whereinsaid chromophore containing group penetrates said skin via apilosebaceous unit.
 10. The method of claim 1, wherein said treatmentmodifies the opening to the infundibulum.
 11. The method of claim 10,wherein said opening is opened.
 12. The method of claim 1, wherein saidchromophore containing group penetrates a sebaceous gland.
 13. Themethod of claim 12, wherein said sebaceous gland is modified.
 14. Themethod of claim 1, wherein said sebaceous gland disorder is acnevulgaris, acne rosacea, or sebaceous gland hyperplasia.
 15. The methodof claim 1, wherein ultrasound is utilized to force said chromophorecontaining group into said spaces.
 16. The method of claim 1, whereinsaid energy is from a pulsed laser dye.
 17. The method of claim 1,wherein said energy is from a diode laser array.
 18. The method of claim1, wherein said spaces in said skin comprise spaces in hair ducts insaid skin not occupied by hair.
 19. The method of claim 1, wherein saidspaces in said skin comprises space within sebaceous glands.
 20. Themethod of claim 1, wherein said spaces in said skin comprise spaceadjacent to sebaceous glands.
 21. A method for modifying the opening tothe infundibulum comprising the steps of: a) topically applying achromophore containing group to the opening to the infundibulum, whereinsaid chromophore containing group is activated by energy whichpenetrates outer layers of epidermis, b) causing a sufficient amount ofsaid chromophore containing group to infiltrate into spaces about saidinfundibulum; and c) exposing said section of skin with sufficientenergy to cause said chromophore containing group to becomephotochemically or photothermally activated, thereby modifying saidopening to the infundibulum.
 22. A method for modifying thepilosebaceous unit comprising the steps of: a) topically applying achromophore containing group to the pilosebaceous unit, wherein saidchromophore containing group is activated by energy which penetratesouter layers of epidermis, b) causing a sufficient amount of saidchromophore containing group to infiltrate the pilosebaceous unit: andc) exposing said section of skin with sufficient energy to cause saidchromophore containing group to become photochemically or photothermallyactivated, thereby modifying the pilosebaceous unit.
 23. The method ofclaim 21, wherein said chromophore containing group is a laser sensitivematerial.
 24. The method of claim 23, wherein said laser sensitivematerial is methylene blue.
 25. The method of claim 22, wherein saidchromophore containing group is a laser sensitive material.
 26. Themethod of claim 25, wherein said laser sensitive material is methyleneblue.